The goal of this Program Project is the identification and testing of vaccines for the prevention and treatment of Trypanosoma cruzi infection and Chagas' disease. Projects 1 and 2 of the program project will use Expression Library Immunization (ELI) and DNA microarrays, respectively, to select a pool of approximately 50 vaccine candidates genes from a T. cruzi genomic expression library with the proven ability to provide protection from T. cruzi infection in mice. Project 3 will focus on optimization of a general immunization strategy using these candidate molecules, defining the optimal mix of candidates molecules needed to obtain maximal protective immunity, and determining the ability of genetic cytokine adjuvants to enhance the immunity further. The range of effectiveness of an the optimized multi-component vaccine will then be tested in murine hosts of different genetic backgrounds, and challenged with diverse parasite strains via different routes. Mice of three different strains will be challenged by either the intraperitoneal, cutaneous, sub- cutaneous, intravenous or oral route either blood-form or metacyclic stage parasites obtained from insects. We will also assess the therapeutic potential of the multi-component vaccine for T. cruzi. Using well- characterized murine models of Chagas' disease to determine a multi- component vaccine for T. Cruzi. Using well-characterized murine models of Chagas' disease to determine if a multi-component vaccine can alter the course and severity of Chagas' disease when given during the chronic phase of the infection. The effect of vaccine delivery both with and without genetic adjuvants on the tissue parasite load and tissue inflammatory response will be monitored. Completion of this project will establish whether or not a prophylactic or therapeutic vaccine for T. cruzi is feasible and will lay the ground work for further evaluation of a multi-component genetic vaccine in other animal models, including primates.